Short and long-term activity-dependent changes in synaptic efficacy are essential to brain function. Experimental evidence indicates that activity-induced long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission are cellular correlates to learning and memory and experience-dependent refinement of neural connections. The molecular mechanisms underlying synaptic plasticity are diverse and can be characterized as presynaptic or postsynaptic, depending on whether neurotransmitter release, or a target neuron's sensitivity to the released transmitter, is modified. Presynaptic LTP and LTD have now been observed across many brain regions, including the hippocampus, both at excitatory and inhibitory synapses, and growing evidence indicates that presynaptic LTP/LTD may underlie important forms of learning. However, the synaptic learning rules for these forms of plasticity are poorly characterized, and our understanding of presynaptic mechanisms lags far behind the postsynaptic side. Presynaptic plasticity can originate entirely in the presynaptic terminal or it may require retrograde signaling from postsynaptic to presynaptic compartments. In the last decade, retrograde signaling emerged as a widely expressed mechanism by which postsynaptic neurons can control their own inputs and, by this means, regulate neural circuits over short and long-time scales. The best characterized retrograde signaling system is the endocannabinoid (eCB) system, and while much has been learned from this system, important knowledge gaps remain for other retrograde messengers including the type of activity required for mobilization, the mechanisms of postsynaptic release and presynaptic action, and ultimately, the precise physiological role of retrograde signaling at a synapse in a given neural circuit. In this research proposal, we will address these outstanding questions by focusing on three distinct hippocampal synapses using state-of-the-art electrophysiology, molecular pharmacology, optogenetics, and live imaging in acute brain slices. Specifically, we will test the hypothesis that presynaptic protein synthesis is necessary for eCB-mediated LTD at inhibitory synapses. In addition, we will determine the mechanism and functional consequence of a novel form of presynaptic LTP at a key, but remarkably understudied, excitatory synapse in dentate gyrus. Finally, we will test the hypothesis that retrograde signaling negatively regulates a powerful detonator synapse. Knowledge derived from these investigations will provide new mechanistic insights on retrograde signaling at central synapses and may also uncover novel roles for presynaptic plasticity in the hippocampal network. A better understanding of presynaptic plasticity represents a significant step forward in the development of strategies to restore synaptic function in diseased brain states, such as autism, neurodegenerative diseases (e.g. Alzheimer's disease, Huntington's disease), schizophrenia, epilepsy and addictive behaviors.